Summary: Project 4 Sali We aim to identify and structurally describe key states on the self-assembly pathways of the A?, PrP, and tau polypeptides, with a broader goal to contribute towards understanding and modulating self-assembly of proteins associated with neurodegenerative diseases. Despite numerous studies, only a few high-resolution structures of states on the biologically relevant aggregation pathways have been determined, and none of them for the key oligomeric states. The essential reasons include the sparseness, noise, and ambiguity of data from any single technique, amplified by the presence of multiple structural states in the compositionally and conformationally heterogeneous samples. To overcome these challenges, integrative structure determination that simultaneously considers data from a variety of different experimental methods will be adapted and used. This approach is implemented in our Integrative Modeling Platform (IMP), an open source software package that provides programmatic support for developing and distributing integrative structure modeling protocols. Here, we will build upon this technical foundation to address the specific problem of mapping protein self- assemblies. The Specific Aims are: (1) Develop computational methods for integrative structural modeling of oligomeric and polymeric self-assemblies of proteins; (2) Determine the structures of key states on the A?, PrP, and tau self-assembly pathways; (3) Predict small-molecule, peptide, and peptide-mimetic modulators of A?, PrP, and tau self-assembly.